Impulsivity, often defined as action without forethought or regard for consequences, is an essential feature of numerous psychiatric conditions (e.g. addiction, bipolar disorder, suicide). The presence of impulsivity in these conditions likely reflects a common neurobiology. Currently there is no single effective treatment for impulsivity across psychiatric illnesses. The proposed work will examine the role the hypothalamic neuropeptide orexin (hypocretin) plays in impulsivity and the potential utility of orexin receptor antagonists in treating conditions characterized by high impulsivity. In Aim 1 the effect of the orexin-1 receptor antagonist SB334867 on impulsive choice in rats will be tested using a delay discounting (DD) task where subjects choose between a small reward available immediately and a larger reward available after a delay. In Aim 2 the effects of orexin gene knockdown (RNAi) on delay discounting will be assessed. Use of DD tasks and RNAi constitute the training aims of this career development award. In Aim 3 RNAi will be used to reduce orexin-1 receptor expression in the ventral tegmental area (VTA) of rats that will perform a DD task or a 5-choice serial reaction time task (5-CSRTT) in which premature responding reflects impulsive action. In Aim 4, viral mediated gene transfer will be used to overexpress secretable orexin in the lateral hypothalamus of rats that will perform DD or 5-CSRTT tasks. In Aim 5 the levels of prepro-orexin or its receptors will be measured in the brains of rats that consistently show either high or low premature responding in the 5-CSRTT. The number of Fos-immunoreactive orexin neurons in high- and low-impulsive animals will also be measured. In Aims 1-3 it is predicted that attenuated orexin transmission achieved by pharmacological or genetic means will reduce measures of impulsivity. Conversely, in Aim 4 genetically elevated orexin is predicted to increase impulsive behavior. In Aim 5, it is anticipated that high-impulsive rats will show higher Fos expression in orexin neurons and higher levels of orexin peptide and its receptors. PUBLIC HEALTH RELEVANCE: A tendency to act without regard to consequences (impulsivity) is common in many mental illnesses. This research will examine whether the neurotransmitter orexin is responsible for impulsive behavior. It will also test a drug that blocks orexin and could be used to treat mental illnesses like addiction or bipolar disorder where highly impulsive behavior can be problematic.